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PEDIATRICS Vol. 110 No. 2 August 2002, pp. 386-388

Small Thymus at Birth: A Predictive Radiographic Sign of Bronchopulmonary Dysplasia

Claudio De Felice, MD*, Giuseppe Latini, MD§,||, Antonio Del Vecchio, MD§, Paolo Toti, MD{ddagger}, Franco Bagnoli, MD* and Felice Petraglia, MD*

* Department of Pediatrics, Obstetrics and Reproduction
{ddagger} Institute of Pathology, University of Siena
§ Division of Pediatrics, Perrino Hospital, Azienda Ospedaliera A. Di Summa, Brindisi, Italy
|| Clinical Physiology Institute (IFC-CNR) National Research Council of Italy, Lecce Section, Italy


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Objective. Emerging evidence indicates a relationship between bronchopulmonary dysplasia (BPD) and chorioamnionitis. Recent data provide evidence of an acute thymic involution in very low birth weight (VLBW) preterm infants and fetuses with histologic chorioamnionitis. We tested the hypothesis that a small thymus detected at birth on the routine chest radiograph is a predictor of BPD in VLBW infants.

Methods. A prospective study was conducted on 400 VLBW preterm infants who survived >4 weeks (mean gestational age: 27.5 weeks [range: 24–30]; mean birth weight: 1010 g [range: 450-1450]). Thymic size was measured on routine chest radiographs taken in the first 6 hours after birth and expressed as the ratio between the transverse diameter of the cardiothymic image at the level of the carina and that of the thorax (CT/T). The accuracy of CT/T for identifying infants with BPD was tested using receiver operating characteristic curve analyses and multivariate logistic regression.

Results. Fifty-one VLBW infants (12.7%) subsequently developed BPD. A small thymus (CT/T <0.28) was observed in 94.1% of the infants with BPD versus 2.9% of the infants without BPD. A small thymus at birth identified infants with BPD with 94.1% sensitivity and 98.3% specificity (odds ratio: 17.8; 95% confidence interval: 5.7–55.4).

Conclusions. A small thymus at birth on the standard chest radiograph can accurately identify VLBW infants who subsequently develop BPD.

Key Words: preterm infant • premature • BPD • very low birth weight • risk factors

Abbreviations: BPD, bronchopulmonary dysplasia • VLBW, very low birth weight • CT/T, cardiothymic to thorax ratio • AUC, area under the curve • CI, confidence interval • IL, interleukin


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Bronchopulmonary dysplasia (BPD) is an important cause of mortality and morbidity in preterm infants. Functional and anatomic changes of BPD develop in approximately 23% to 26% of very low birth weight (VLBW) infants and 30% of neonates with birth weights <1000 g surviving initial hospitalization.1–4 The pathogenesis of BPD remains unclear, although several risk factors have been identified.5 Oxygen toxicity, mechanical injury, volutrauma, and antenatal or postnatal inflammatory response have been associated with injury to the immature lung and the development of BPD.1–5 Emerging evidence indicates that BPD may be related to intrauterine cytokine activation linked to chorioamnionitis6,7 and that histologic chorioamnionitis is associated with acute thymic involution.8,9 In the present study, the hypothesis that a small thymus detected at birth on the routine chest radiograph may be a predictor of BPD in VLBW preterm infants was analyzed.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Subjects
A total of 400 consecutive VLBW (<1500 g) newborn infants who were admitted to the neonatal intensive care unit and survived >4 weeks were recruited (216 boys, 184 girls; mean gestational age [range]: 27.5 weeks [24–30 weeks]; birth weight 1010 g [450–1450 g]). Exclusion criteria were major malformations, primary immunodeficiency disorders, or mediastinal diseases. A diagnosis of BPD was made on the basis of all of the following criteria: 1) requirement of intermittent positive-pressure ventilation ≥3 days during the first week after birth, 2) clinical signs of chronic respiratory disease persistent for >28 days, 3) requirement of supplemental oxygen for >28 days to maintain a PaO2 >50 mmHg, and 4) typical changes on the chest radiograph. In the case of death, the diagnosis was confirmed on the basis of the autopsy.9,10 Clinical and radiographic severity of BPD was determined as described by Toce et al.11 Data collection was performed prospectively. Clinical information was collected independently by 2 neonatologists, who were unaware of the radiologic findings. Chest radiographs were performed according to widely recognized technique standards. In particular, at least 7 intercostal spaces and the eighth rib were bilaterally visible, and the right to left hemidiaphragm length ratio was (mean ± standard deviation) 1.04 ± 0.10. Thymic size was assessed as described previously.8,12 In brief, the width of the cardiothymic silhouette was measured at the level of the carina in routine, anteroposterior supine chest radiographs taken in the first 6 hours after birth (median: 2 hours; range: 0.1–6 hours). Thymic size was expressed as the ratio between the transverse diameter of the cardiothymic image at the level of the carina and that of the thorax (CT/T). Approval of the Institutional Review Board and informed consent from the parents were obtained.

Statistical Analysis
Data are expressed as means ± standard deviation for continuous normally distributed data and medians with interquartile range (25th and 75th percentiles) for nonnormal distributions. The t test or Mann-Whitney U test, and {chi}2 test or Fisher exact test were used to compare continuous normally distributed data, nonparametric continuous data, and categorical data, respectively. Discrimination (the ability of the model to identify BPD-positive and BPD-negative infants) was tested using receiver operating characteristic curves, and an area under the curve (AUC) value above 0.80 was accepted to indicate a good discrimination.13 Comparisons of the AUCs were evaluated by the deLong method.14 Calibration (estimation of the probability with which the deviation of observed from expected values is likely to occur) was tested using the {chi}2 statistics to compare the observed values (according to the classification of the infants into the 2 groups BPD positive vs BPD negative) with the expected values (according to birth weight, gestational age, and CT/T values). Data were analyzed by multivariate logistic regression models15 with BPD as the dependent variable and birth weight, gestational age, antenatal steroids, vaginal delivery, pregnancy-induced hypertension, preterm premature rupture of the membranes, 1-minute Apgar score, surfactant replacement, and CT/T ratio. Predictors with P values of <.25 at univariate analysis were tested in the models. Gestational age was entered as a continuous variable, whereas birth weight was entered as either a categorical (<1000 g or ≥1000 g) or a continuous variable. Because of the collinearity between birth weight and gestational age, one or the other of these 2 variables was entered in the models. STATISTICA software (StatSoft, Tulsa, OK), SPSS release 6.1 statistical package (SPSS Inc, Chicago, IL), and MedCalc software (MedCalc Software, Mariakerke, Belgium) were used. A 2-sided P value of <.05 was considered to be statistically significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Fifty-one of 400 infants (26 boys, 25 girls) were categorized as BPD positive, and 349 (190 boys, 159 girls) were categorized as BPD negative. Relevant clinical information on the 2 groups of infants is provided in Table 1. Clinical and radiographic severity scores for the BPD infants were 8.0 ± 1.87 (range: 6–11) and 7.0 ± 2.1 (range: 5–10). BPD infants showed a significantly lower CT/T ratio than the BPD-negative group (P < .0001). A CT/T cutoff of ≤0.28, as derived by receiver operating characteristic curve analysis, identified BPD infants with a sensitivity of 94.1% (95% confidence interval [CI]: 83.7–98.7), specificity of 98.3% (95% CI: 96.3–99.4), positive predictive value of 88.9%, and negative predictive value of 99.1% (Table 2) with adequate model calibration ({chi}2 = 0.03, df = 1, P = .86). A small thymus (CT/T ≤0.28) was present in 94.1% (48 of 51) of the BPD-positive infants versus 2.9% (10 of 349) in the BPD-negative group (unadjusted relative risk: 32.85; 95% CI: 17.76–60.73; P < .0001). Discrimination accuracy for birth weight and gestational age in predicting BPD is also shown (Table 2). The differences between the AUC values for CT/T and those of both gestational age and birth weight were statistically significant (CT/T vs gestational age: 0.249 ± 0.036 [95% CI: 0.178–0.320], P < .0001; CT/T vs birth weight: 0.273 ± 0.038 [95% CI: 0.199–0.347], P < .0001). The final, most parsimonious logistic regression model retained small thymus (≤0.28; adjusted odds ratio [OR]: 17.8; 95% CI: 5.7–55.4; P < .0001) and either birth weight <1000 g (OR: 3.5; 95% CI: 1.5–8.5; P = .0047) or gestational age (OR: 1.5; 95% CI: 1.3–1.8; P < .0001). Conversely, vaginal delivery (P = .051), preterm premature rupture of the membranes >18 hours (P = .065), pregnancy-induced hypertension (P = .31), use of antenatal steroids (P = .32), 1-minute Apgar score ≤3 (P = .35), and surfactant supplementation (P = .61) were not included in the equation.


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  		TABLE 1. Comparisons Between VLBW Infants With and Without BPD: Relevant Prenatal and Neonatal Characteristics

 

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  		TABLE 2. Predictive Accuracy of CT/T, Gestational Age, and Birth Weight in Identifying Infants With BPD: Results of Receiver-Operating Characteristic Curve Analyses

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
BPD is usually defined as oxygen dependency at 28 days’ postnatal age or 36 weeks’ postconceptional age.16 Postmortem10 and respiratory mechanics studies17 have shown that functional and anatomic changes of BPD develop in the early neonatal period (first week), well before the 28 days or 36 weeks of the usual clinical definitions. In this regard, the last definition was not applicable because of the very low incidence of oxygen-dependency at 36 weeks in our population.18

Recently, we showed a significant relationship between chorioamnionitis and a small thymus as a result of extensive lymphocyte depletion, and there is increasing evidence that inflammation plays an important role in the pathogenesis of BPD,4–7 although additional studies are needed to investigate the relations between thymus size, chorioamnionitis, and BPD.

In experimental models, acute thymic involution has been related to antenatal glucocorticoid but not to endotoxin administration.19,20 However, it is known that findings observed in animal models cannot be thoroughly applicable to humans. Moreover, a dramatic thymic lymphocyte depletion after exposure to interleukin (IL)-1{alpha} and IL-1ß in mice has been reported,21 and the administration of IL-1ß to pregnant rats has been shown to activate the hypothalamo-pituitary-adrenal axis in the mother and reduce both maternal and fetal thymic weights.22 Furthermore, the dose of the antenatal steroid used was standard and has not been documented to be sufficient for shrinking the thymus.

Both ultrasonography and chest radiograph have been used to estimate thymic size in preterm infants,8,23 but chest radiograph is more widely used as a routine diagnostic procedure in sick VLBW infants. The results of this study indicate that a standard chest radiograph showing a small thymus at birth accurately identifies VLBW infants who subsequently develop BPD. The evidence of a small thymus at birth suggests that the mechanisms that initiate the lung injury that leads to BPD begin antenatally and are possibly linked to a fetal systemic inflammatory response.6,24 Additional studies are needed to explain more precisely how prenatal inflammation can initiate injury in fetal lungs and how other potential factors, such as mechanical ventilation, volutrauma, and leakage of plasticizers, are involved in propagating a local and possibly systemic inflammatory response after birth.1,25,26 The present findings may provide rationale for intervention for prevention of BPD within the first day after birth.


   ACKNOWLEDGMENTS
 
We thank Gordon B. Avery, MD, PhD, Emeritus Professor, Children’s National Medical Center (Seattle, WA) and Eduardo Bancalari, MD, Department of Pediatrics Division of Neonatology School of Medicine University of Miami (Miami, FL) for invaluable advice; Dr Luigi DiLeo and Alessandra Lombardi for data collection; and Katie Henry for editorial assistance, University of Siena.


   FOOTNOTES
 
Received for publication Oct 3, 2001; Accepted Feb 19, 2002.

Reprint requests to (C.D.) U.O. Terapia Intensiva Neonatale, Dipartimento di Pediatria Ostetricia e Medicina della Riproduzione, Viale M. Bracci 16, I-53100 Siena, Italy. E-mail: defelice.claudio{at}libero.it


   REFERENCES
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 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
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PEDIATRICS (ISSN 1098-4275). ©2002 by the American Academy of Pediatrics

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